+

WO2003095471A2 - Produits pharmaceutiques pour traiter des dysfonctionnements aigus de la circulation de la veine porte et de la veine hepatique - Google Patents

Produits pharmaceutiques pour traiter des dysfonctionnements aigus de la circulation de la veine porte et de la veine hepatique Download PDF

Info

Publication number
WO2003095471A2
WO2003095471A2 PCT/EP2003/004861 EP0304861W WO03095471A2 WO 2003095471 A2 WO2003095471 A2 WO 2003095471A2 EP 0304861 W EP0304861 W EP 0304861W WO 03095471 A2 WO03095471 A2 WO 03095471A2
Authority
WO
WIPO (PCT)
Prior art keywords
acid
formula
defined above
carbon atoms
use according
Prior art date
Application number
PCT/EP2003/004861
Other languages
English (en)
Other versions
WO2003095471A3 (fr
Inventor
Piero Del Soldato
Giancarlo Acuto
Original Assignee
Nicox S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CA002485146A priority Critical patent/CA2485146A1/fr
Priority to IL16434503A priority patent/IL164345A0/xx
Priority to EP03720562A priority patent/EP1504020A2/fr
Priority to KR10-2004-7018429A priority patent/KR20050000543A/ko
Priority to JP2004503485A priority patent/JP2005526127A/ja
Priority to NZ535740A priority patent/NZ535740A/en
Application filed by Nicox S.A. filed Critical Nicox S.A.
Priority to AU2003224154A priority patent/AU2003224154A1/en
Priority to MXPA04011233A priority patent/MXPA04011233A/es
Priority to US10/512,856 priority patent/US20060094664A1/en
Publication of WO2003095471A2 publication Critical patent/WO2003095471A2/fr
Publication of WO2003095471A3 publication Critical patent/WO2003095471A3/fr
Priority to NO20045437A priority patent/NO20045437L/no

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives

Definitions

  • the present invention relates to the use of drugs for the acute treatment of hepatic and portal venous circulation disorders or hemodynamic decompensation.
  • the present invention relates to the use of drugs for the acute treatment of hepato-portal tract disorders and not for the chronic treatment of hepatic diseases, such as for example cirrhosis.
  • the hepatic and portal venous circulation disorders are characterized by an improved intrahepatic flow resistance or by an increase of portal vein flow, due to a vessel occlusion, or congestion, generally caused by a liver disorder.
  • the acute treatment is only directed to reduce the increase of the portal pressure, whereas the chronic treatment, that starts in the early phase of the disease, has merely the aim to limit the progress of said disease.
  • the present invention relates to a treatment able to decrease the portal pressure in acute phase.
  • portal blood flow may have serious clinic consequences for a patient, such as: development of portosystemic collateral circulation (gastroesophageal varices) direct shunting of portal blood into vena cava (hepatic encephalopathy) abdominal viscera congestion (malabsorption) and splenomegaly (hypersplenism with platletspenia) - ascites.
  • portosystemic collateral circulation gastroesophageal varices
  • vena cava hepatic encephalopathy
  • abdominal viscera congestion malabsorption
  • splenomegaly hyperplenism with platletspenia
  • Further factors that may contribute to the appearance of said disorders can be alcohol-related liver damage, congenital hepatic fibrosis, drug poisoning, autoimmune diseases .
  • Acute bleeding from esophageal varices is the most common clinical picture of these hepatic or portal venous circulation disorders.
  • patients present with sudden painless upper gastrointestinal hemorrhage, often massive.
  • Acute bleeding is a very serious phenomenon that must be treated for avoiding consequences also fatal for the patient.
  • variceal bleeding The pharmacological therapy for the acute treatment of variceal bleeding consists in using drugs able to reduce the portal pressure.
  • Vasopressin, somatostatin and its analogues may be mentioned.
  • vasopressin exhibits side effects such as mesenteric and myocardial ischemia.
  • effectiveness of these drugs in treatment of acute bleeding has not been established.
  • ⁇ - blockers such as for example propranolol, nadolol, timolol, etc.
  • ⁇ - blockers such as for example propranolol, nadolol, timolol, etc.
  • the ⁇ -blockers are active in reducing portal flow resistance but exhibit the following collaterals: they possess side effects on cardiovascular and respiratory system. For this reason, they can not be administered to patients having cardiovascular problems, asthma, COPD (chronic obstructive pulmonary disease) etc., - in a few subjects intolerance of these drugs occurred, thus developing dyspnoea and bronchospnea, dyspnoea and cardiopathy, asthenia, gastric intolerance and hepatic encefalopathy .
  • vasodilators For the acute treatment of hepatic and portal venous circulation disorders also vasodilators have been used, such as for example isosorbide mononitrate .
  • vasodilators For the acute treatment of hepatic and portal venous circulation disorders also vasodilators have been used, such as for example isosorbide mononitrate .
  • their systemic vasodilatatory action may be not well tolerated by patients suffering from portal hypertension, in that they can give rise to a reduction of systemic pressure.
  • the present invention relates to the use for the acute treatment of hepatic or portal venous circulation disorders of compounds having the following formula (I)
  • nlX is an integer of from 0 to 10, preferably of from 1 to
  • nllx is an integer of from 1 to 10, preferably of from 1 to
  • R-TIIX, RTIIX- are the same or different and are H or
  • RTIIX, R-TIIX' are H ;
  • Y 3 is a 5 or 6 member heterocyclic ring comprising one or two heteroatoms selected from nitrogen, oxygen or sulfur, said ring being saturated, unsaturated or aromatic;
  • Y 0 selected from:
  • R' is C 3. -C 20 straight or branched alkyl, preferably with 2-6 carbon atoms, or cycloalkylene with 5-7 carbon atoms, one or more carbon atoms in cycloalkylene ring being eventually replaced by heteroatoms, and the ring having optionally type R' side chains, in which R' is as defined above; or one of the following groups:
  • nf is an integer of from 1 to 6, preferably of from 1 to 4 carbon atoms
  • R lf H, CH 3 and nf is as defined above;
  • Y Ar that is selected from:
  • n3 is an integer of from 0 to 3 and n3 ' an integer
  • n3 and n3 ' are as defined above,
  • the B precursor is selected from the following: amino acids, preferably selected from L-carnosine (formula CI) , anserine (CII) , selenocysteine (CIII) , selenomethionine (CIV) , penicillamine (CV) , N- acetylpenicillamine (CVI) , cysteine (CVII) , N- acetylcysteine (CVIII) , glutathione (CIX) or esters thereof, preferably ethyl or isopropyl ester, aspartic acid (PI) , hystidine (PI I) , 5-hydroxytryptophan (PHI) :
  • amino acids preferably selected from L-carnosine (formula CI) , anserine (CII) , selenocysteine (CIII) , selenomethionine (CIV) , penicillamine (CV) , N- ace
  • PI PII
  • PHL gallic acid
  • DII ferulic acid
  • DIII gentisic acid
  • DIV citric acid
  • DIV caffeic acid
  • DVI dihydroxycaffeic acid
  • DVII p-coumaric acid
  • VIII vanillic acid
  • NH dihydroxymaleic acid
  • NASH nordihydroguaiaretic acid
  • El quercetin
  • EH catechin
  • EIII catechin
  • EIV kaempferol
  • SEP sulfuretin
  • EVIII hydroquinone
  • gossypol EIX
  • reductic acid EX
  • methoxyhydroquinone EXI
  • hydroxyhydroquinone EXII
  • propyl gallate EXIII
  • EXXIV saccharose
  • ECI ascorbic
  • ECU isoascorbic
  • ECU p-coumaric alcohol
  • ECIV 4- hydroxy-phenylethyl alcohol
  • ECU 2-thiouracil
  • bonds between the drug radical and X 2 as well as between X 2 and Y can be independently of ester, thioester or amid type.
  • Y 3 of bivalent radical C is selected from the following bivalent radicals:
  • the preferred radicals for Y 3 are the following: (Y12), with both the free valences in ortho position as to the nitrogen atom; (Y16) with both the free valences attached to the nitrogen atoms; (Yl) , 3 , 5-disostituted pyrazole; (Y19) , wherein the free valence is para-standing on the ring as to the nitrogen atom.
  • the Y precursors having the formula (IH P ) in which the free valence on oxygen atom is saturated with H and the free valence on end carbon atom is saturated with a carboxylic or oxydrilic group, are available on the market or they can be prepared according to methods well-known in the art .
  • the compounds according to the present invention when at least a functional group that may be salified with acid is present, for example an amine group, can be transformed in the corresponding salts.
  • a process for obtaining salts is the following: when into the molecule a basic nitrogen atom is present, the reaction with an equimolar amount of the corresponding organic or inorganic acid is carried out in an organic solvent, such as acetonitrile, tetrahydrofuran.
  • organic acids are oxalic, tartaric, maleic, succinic, citric and trifluoroacetic acids.
  • inorganic acid examples include nitric, hydrochloric, sulphuric and phosphoric acids.
  • Compounds that are employed for the therapeutic uses according to the present invention may be obtained as described for example in WO 00/61604.
  • the precursor compounds employed in the present invention may be in racemic form or as diastereomers mixture, as single enantiomers or diastereomers. Should geometric asymmetrie be present, the compounds can be used into the cis or trans form.
  • the compounds object of the present invention are formulated into the corresponding pharmaceutical compositions, also in sustained release form, for parenteral or oral use, for example sublingual, inhalation, transdermic, as suppositories or enema, according to techniques well-known in the art: see for example "Remington's Pharmaceutical Sciences” 15 th Ed.
  • the active ingredient molar amount in said formulations is generally equal or lower than the amount of the corresponding drug precursor.
  • the daily dose that can be administered is equal to or eventually lower than the dose of the precursor drug.
  • the precursor daily dose can be found for example in "Physician's Desk Reference".
  • the compounds preferred for the use according to the present invention are those in which B arises from the precursor ferulic acid, in particular the more preferred compound is (3 ⁇ , 5 ⁇ , 7 ⁇ ) -3, 7-dihydroxycholan-24-oic acid 2-methoxy-4 [3- [4- (nitrooxy) butoxy] -3-oxo-l-propenyl] phenyl ester having the following formula:
  • the preferred group Y is of Y 0 type, in particular the alkylene group R'O, R' being C 3 - C 6 alkyl.
  • a particular preferred compound is (3 ⁇ ,5 ⁇ ,7 ⁇ )- 3 , 7-dihydroxycholan-24-oic acid 4- (nitrooxy) butyl ester of the following formula:
  • the drugs of the present invention employed for the acute treatment of hepatic and portal hemodynamic decompensation, possess surprisingly and unexpectedly optimal results in reducing portal pressure.
  • the precursors of the invention compounds such as for example ursodeoxycholic acid, are effective in the chronic treatment of hepatic disorders but not for reducing portal pressure after an acute treatment.
  • invention compounds for treating the acute phase of hepatic disorders when a high portal pressure is occurring.
  • high portal pressure conditions for example 500% as to the basal value, induced by a norepinephrine treatment, the invention compounds are able to reduce the portal pressure without influencing the systemic hemodynamic parameters.
  • the administration of the compounds of the invention is carried out for very short cycles, generally a few days, at most a week, whereas in chronic treatment the administration occurs for long periods of time, at least for eight weeks, sometime months, in that a cirrhosis has been developed in liver. Therefore, it was not foreseeable that treatments having so a short term could be able to show a so high activity in reducing the portal pressure in acute phase treatment .
  • EXAMPLE 1 Effect of ursodeoxycholic acid and of (3 ⁇ , 5 ⁇ , 7 ⁇ ) -3 , 7- dihydroxycholan-24-oic acid 2-methoxy-4 [3- [4-
  • ursodeoxycholic acid nitrooxyderivative here employed has been prepared as described in Example 1 of patent application PCT WO 00/61,604.
  • Group 1 control group treated with carrier (1% w/v water suspension of carboxymethylcellulose) ;
  • Group 2 treated with NO-urso at a dose of 28 mg/kg (0.04 mmol/kg) , twice a day;
  • Group 3 treated with ursodeoxycholic acid (urso in table) at a dose of 15 mg/kg (0,04 mmol/kg), twice a day.
  • the rested compounds have been administered by intragastric cannula in 1% water suspension of carboxymethylcellulose .
  • MAP systemic pressure
  • PP portal pressure
  • the rat liver was then firstly perfused with norepinephrine solution (1 ⁇ M) in order to induce an intrahepatic circulation constriction. Afterwards, in groups 2 and 3 a single infusion with a 1 mM solution of each of the tested compounds was carried out and portal pressure variations have been monitored.
  • NO-urso reduces intrahepatic resistance induced both by bile duct constriction and norepinephrine (NE) administration.
  • NE norepinephrine
  • administration of NO-urso unlike that of ursodeoxycholic acid, is able to reduce intrahepatic resistance in animals having high intrahepatic resistance and/or marked hepatic alteration.
  • NO-urso induced a portal pressure reduction of 3 mmHg.
  • the rats treated with Urso showed instead an increase of 2 mmHg with respect to controls.
  • the portal pressure reduction obtained by NO-urso perfusion resulted statistically significant (p ⁇ 0.01).
  • Ursodeoxycholic acid (0.5 g) was reacted with sodium ethylate (0.09 g) in DMF to give the corresponding sodium salt.
  • This solution was dropped into a solution of 1,4- dibromobutane (0.263 g) in DMF. The mixture thus obtained was allowed to stand overnight under stirring at room temperature.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne l'utilisation de composés et de leurs sels de formule (I), telle qu'indiquée dans le descriptif de l'invention, pour préparer des produits pharmaceutiques destinés au traitement de dysfonctionnement aigus de la circulation de la veine porte et de la veine hépatique.
PCT/EP2003/004861 2002-05-14 2003-05-09 Produits pharmaceutiques pour traiter des dysfonctionnements aigus de la circulation de la veine porte et de la veine hepatique WO2003095471A2 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
IL16434503A IL164345A0 (en) 2002-05-14 2003-05-09 Drugs for the treatment of acute dysfunctions of portal and hepatic venous circulation
EP03720562A EP1504020A2 (fr) 2002-05-14 2003-05-09 Produits pharmaceutiques pour traiter des dysfonctionnements aigus de la circulation de la veine porte et de la veine hepatique
KR10-2004-7018429A KR20050000543A (ko) 2002-05-14 2003-05-09 간문맥 및 간 정맥순환 급성기능장애의 치료를 위한데옥시콜산유도체들
JP2004503485A JP2005526127A (ja) 2002-05-14 2003-05-09 門脈および肝静脈循環の急性機能不全の治療のためのデオキシコール酸誘導体
NZ535740A NZ535740A (en) 2002-05-14 2003-05-09 Deoxycholic acid derivatives for the treatment of acute dysfunctions of portal and hepatic venous circulation
CA002485146A CA2485146A1 (fr) 2002-05-14 2003-05-09 Produits pharmaceutiques pour traiter des dysfonctionnements aigus de la circulation de la veine porte et de la veine hepatique
AU2003224154A AU2003224154A1 (en) 2002-05-14 2003-05-09 Deoxycholic acid derivatives for the treatment of acute dysfunctions of portal and hepatic venous circulation
MXPA04011233A MXPA04011233A (es) 2002-05-14 2003-05-09 Derivados de acido desoxicolico para el tratamiento de disfunciones agudas de circulacion venosa portal y hepatica.
US10/512,856 US20060094664A1 (en) 2002-05-14 2003-05-09 Deoxycholic acid derivatives for the treatment of acute dysfunctions of portal and hepatic venous circulation
NO20045437A NO20045437L (no) 2002-05-14 2004-12-13 Medikamenter for behandling av akutte dysfunksjoner i portavenesirkulasjon og hepatisk sirkulasjon

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT2002MI001025A ITMI20021025A1 (it) 2002-05-14 2002-05-14 Farmaci per il trattamento acuto di disfunzioni del circolo venoso epatico e portale
ITMI2002A001025 2002-05-14

Publications (2)

Publication Number Publication Date
WO2003095471A2 true WO2003095471A2 (fr) 2003-11-20
WO2003095471A3 WO2003095471A3 (fr) 2004-04-01

Family

ID=11449892

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2003/004861 WO2003095471A2 (fr) 2002-05-14 2003-05-09 Produits pharmaceutiques pour traiter des dysfonctionnements aigus de la circulation de la veine porte et de la veine hepatique

Country Status (16)

Country Link
US (1) US20060094664A1 (fr)
EP (1) EP1504020A2 (fr)
JP (1) JP2005526127A (fr)
KR (1) KR20050000543A (fr)
CN (1) CN100347186C (fr)
AU (1) AU2003224154A1 (fr)
CA (1) CA2485146A1 (fr)
IL (1) IL164345A0 (fr)
IT (1) ITMI20021025A1 (fr)
MX (1) MXPA04011233A (fr)
NO (1) NO20045437L (fr)
NZ (1) NZ535740A (fr)
PL (1) PL373117A1 (fr)
RU (1) RU2299886C2 (fr)
WO (1) WO2003095471A2 (fr)
ZA (1) ZA200407911B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100513415C (zh) * 2005-08-03 2009-07-15 中国人民解放军军事医学科学院毒物药物研究所 胆汁酸衍生物及其医药用途
CN101439187B (zh) * 2007-11-19 2011-11-30 中国人民解放军军事医学科学院毒物药物研究所 胆汁酸-抗肝炎病毒药物偶合物及其制药用途

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101157740B1 (ko) * 2010-03-26 2012-06-25 성균관대학교산학협력단 설퍼레틴 및 약학적으로 허용되는 이의 염을 포함하는 신경계 질환의 예방 및 치료용 약학 조성물
DE102020006049A1 (de) 2020-10-02 2022-04-07 Radim Vlcek Desoxycholsäure sowie deren Verbindungen zur Verwendung bei der Behandlung von Erkrankungen

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5837698A (en) * 1996-05-02 1998-11-17 G. D. Searle & Co. Steroid nitrite and nitrate ester derivatives useful as anti-inflammatory drugs
IL123998A (en) * 1998-04-08 2004-09-27 Galmed Int Ltd Conjugates of bile salts and pharmaceutical preparations containing them
IT1311922B1 (it) * 1999-04-13 2002-03-20 Nicox Sa Composti farmaceutici.
ES2218222T3 (es) * 1999-09-22 2004-11-16 Aventis Pharma Deutschland Gmbh Conjugados de 4-bencilaminoquinolinas con acidos biliares y sus heteroanalogos, procedimiento para su preparacion, medicamentos que contienen estos compuestos y su uso.

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100513415C (zh) * 2005-08-03 2009-07-15 中国人民解放军军事医学科学院毒物药物研究所 胆汁酸衍生物及其医药用途
CN101439187B (zh) * 2007-11-19 2011-11-30 中国人民解放军军事医学科学院毒物药物研究所 胆汁酸-抗肝炎病毒药物偶合物及其制药用途

Also Published As

Publication number Publication date
RU2004132864A (ru) 2005-06-27
AU2003224154A1 (en) 2003-11-11
RU2299886C2 (ru) 2007-05-27
CN100347186C (zh) 2007-11-07
ZA200407911B (en) 2005-07-01
NZ535740A (en) 2006-10-27
WO2003095471A3 (fr) 2004-04-01
MXPA04011233A (es) 2005-01-25
CA2485146A1 (fr) 2003-11-20
US20060094664A1 (en) 2006-05-04
NO20045437L (no) 2004-12-13
JP2005526127A (ja) 2005-09-02
PL373117A1 (en) 2005-08-08
CN1653083A (zh) 2005-08-10
IL164345A0 (en) 2005-12-18
ITMI20021025A0 (it) 2002-05-14
ITMI20021025A1 (it) 2003-11-14
KR20050000543A (ko) 2005-01-05
EP1504020A2 (fr) 2005-02-09

Similar Documents

Publication Publication Date Title
JP2016034946A (ja) ステロイド性ｃｙｐ１７阻害剤／抗アンドロゲン剤の新しいプロドラッグ
RU2240325C2 (ru) Стероидное соединение, фармацевтические композиции
JP5795312B2 (ja) １７−ヒドロキシ−１７−ペンタフルオロエチル−エストラ−４，９（１０）−ジエン−１１−アリール誘導体、その製造方法、その誘導体を利用した諸疾患の治療
MXPA01010213A (es) Compuestos farmaceuticos.
CA2274779A1 (fr) Composes aminosterol-esters
US20060052594A1 (en) New corticosteroids
AU2003210161A1 (en) New corticosteroids
US5639744A (en) Bile acids derivatives useful in the therapy of the biliary calculosis from cholesterol and of the pathologies caused by cholestasis
WO2003095471A2 (fr) Produits pharmaceutiques pour traiter des dysfonctionnements aigus de la circulation de la veine porte et de la veine hepatique
JP2007517878A (ja) エチニルエストラジオールのジ−ステロイド型プロドラッグ
JPWO2019148293A5 (fr)
CN100513415C (zh) 胆汁酸衍生物及其医药用途
US6596713B1 (en) Steroid esters and amides, process for their production and their pharmaceutical use
CN101182331A (zh) 阿德福韦酯胆酸类衍生物及其制备方法和用途
CN107056819B (zh) 一种预防和治疗心肌缺血的药物及其制备方法
WO2003059870A1 (fr) Derives sulfonamide n-substitues et medicaments preventifs ou therapeutiques pour soigner le diabete renfermant ces derives
WO2013012998A1 (fr) Inhibiteurs de kinase tak1, compositions et utilisations associées
WO2010054565A1 (fr) Promédicament hydrosoluble du (r)-(-)-bicalutamide, son procédé de préparation et ses utilisations
US5616741A (en) Process for the preparation of glycine-conjugated bile acids
CA2548127A1 (fr) Nitro-oxyderives de medicaments contre l'hypertension
WO2009024022A1 (fr) Conjugués acides gras-acides biliaires et leurs utilisations médicales
EP1623713A1 (fr) Combinaisons d'antisetrogène et d'inhibteurs de l'aromatase
JP2007532688A (ja) １７α−フルオロ−１７β−ヒドロキシイミノメチルステロイド、それらを製造する方法および前記化合物を含んでなる医薬組成物
JPH10237096A (ja) グルタチオン誘導体およびそれを含有するｇｓ−ｘポンプ阻害剤
MXPA98010825A (fr)

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 164345

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2003720562

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2004/07911

Country of ref document: ZA

Ref document number: 200407911

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 535740

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2485146

Country of ref document: CA

Ref document number: 20038102110

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 2003224154

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 373117

Country of ref document: PL

WWE Wipo information: entry into national phase

Ref document number: PA/a/2004/011233

Country of ref document: MX

Ref document number: 2004503485

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 1020047018429

Country of ref document: KR

ENP Entry into the national phase

Ref document number: 2004132864

Country of ref document: RU

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 1020047018429

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 2003720562

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2006094664

Country of ref document: US

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 10512856

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 10512856

Country of ref document: US

WWW Wipo information: withdrawn in national office

Ref document number: 2003720562

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载